Aerosolization apparatus with removable mouthpiece

ABSTRACT

An aerosolization apparatus comprises a body having an inlet, an endpiece having an outlet, the endpiece being connectable to the body to define a chamber, wherein the chamber is sized to receive a capsule containing a pharmaceutical formulation in a manner which allows the capsule to move within the chamber. The apparatus further includes a connection mechanism to provide selective connection of the endpiece to the body, wherein a rotational force between the endpiece and the body is needed to connect or disconnect the endpiece from the body, the rotational force being applied about an axis passing through the chamber. When a user inhales, air enters into the chamber through the inlet so that the pharmaceutical formulation is aerosolized within the chamber and the aerosolized pharmaceutical formulation is delivered to the user through the outlet. The connection mechanism prevents inadvertent disconnection of the endpiece from the body.

RELATED APPLICATIONS

The present application claims the benefit of U.S. ProvisionalApplication No. 60/336,320 filed on Nov. 14, 2001.

BACKGROUND

The need for effective therapeutic treatment of patients has resulted inthe development of a variety of pharmaceutical formulation deliverytechniques. One traditional technique involves the oral delivery of apharmaceutical formulation in the form of a pill, capsule, elixir, orthe like. However, oral delivery can in some cases be undesirable. Forexample, many pharmaceutical formulations may be degraded in thedigestive tract before they can be effectively absorbed by the body.Inhaleable drug delivery, where an aerosolized pharmaceuticalformulation is orally or nasally inhaled by a patient to deliver theformulation to the patient's respiratory tract, has proven to be aparticularly effective and/or desirable alternative. For example, in oneinhalation technique, a pharmaceutical formulation is delivered deepwithin a patient's lungs where it may be absorbed into the blood stream.Many types of inhalation devices exist including devices that aerosolizea dry powder, devices comprising a pharmaceutical formulation stored inor with an inhaleable propellant, devices which use a compressed gas toaerosolize a liquid pharmaceutical formulation, and similar devices.

In one dry powder aerosolization technique, a capsule containing aninhaleable dry powder is loaded into a chamber in an aerosolizationdevice. Within the chamber, the dry powder is at least partially emptiedand dispersed to aerosolize the dry powder so that it may be inhaled bya patient. However, in conventional devices, the manner of accessing thechamber may often lead to device inconsistencies and/or failures. Also,the dry powder in the cavity can cause the access mechanism to becomeless effective at efficiently opening and closing.

Therefore, it is desirable to improve the manner of accessing anaerosolization device chamber. It is further desirable to access thechamber in a manner that reduces device inconsistencies and/or failures.It is still further desirable to access the cavity so that debris in thecavity will have reduced adverse affects on the functioning of thedevice.

SUMMARY

The present invention satisfies these needs. In one aspect of theinvention an aerosolization apparatus comprises a body and an endpiece,the body and endpiece being connectable to one another by a connectionmechanism that prevents inadvertent disconnection of the parts.

In another aspect of the invention, an aerosolization apparatuscomprises a body having an inlet, an endpiece having an outlet, theendpiece being connectable to the body to define a chamber, wherein thechamber is sized to receive a capsule containing a pharmaceuticalformulation in a manner which allows the capsule to move within thechamber, a connection mechanism to provide selective connection of theendpiece to the body, wherein a rotational force between the endpieceand the body is needed to connect or disconnect the endpiece from thebody, the rotational force being applied about an axis passing throughthe chamber, and a puncturing mechanism capable of providing an openingin the capsule, whereby when a user inhales, air enters into the chamberthrough the inlet so that the pharmaceutical formulation is aerosolizedwithin the chamber and the aerosolized pharmaceutical formulation isdelivered to the user through the outlet.

In another aspect of the invention, an aerosolization apparatuscomprises a body having an inlet, an endpiece having an outlet, theendpiece being connectable to the body to define a chamber, wherein thechamber is sized to receive a capsule containing a pharmaceuticalformulation in a manner which allows the capsule to move within thechamber, a connection mechanism to provide selective connection of theendpiece to the body, wherein the connection mechanism comprisesengageable threads, and a puncturing mechanism capable of providing anopening in the capsule, whereby when a user inhales, air enters into thechamber through the inlet so that the pharmaceutical formulation isaerosolized within the chamber and the aerosolized pharmaceuticalformulation is delivered to the user through the outlet.

In another aspect of the invention, an aerosolization apparatuscomprises a body having an inlet, an endpiece having an outlet, theendpiece being connectable to the body to define a chamber, wherein thechamber is sized to receive a capsule containing a pharmaceuticalformulation in a manner which allows the capsule to move within thechamber, a connection mechanism to provide selective connection of theendpiece to the body, wherein the connection mechanism comprises aprotrusion that is receivable within a slot, the slot comprising alongitudinally extending portion and a transversely extending portion,and a puncturing mechanism capable of providing an opening in thecapsule, whereby during inhalation air enters into the chamber throughthe inlet so that the pharmaceutical formulation is aerosolized withinthe chamber and the aerosolized pharmaceutical formulation is deliveredto the user through the outlet.

In another aspect of the invention, a method of providing an aerosolizedpharmaceutical formulation comprises providing a body and an endpiece,the endpiece being connectable to the body when a rotational force isapplied thereto to define a chamber, the chamber being sized to receivea capsule containing a pharmaceutical formulation, wherein the rotationforce is applied about an axis that passes through the chamber, andaerosolizing the pharmaceutical formulation when a user inhales bycausing air to flow through an inlet in the body, within the chamber,and through an outlet in the endpiece to provide the aerosolizedpharmaceutical formulation to the user.

In another aspect of the invention, a method of aerosolizing apharmaceutical formulation comprises inserting a capsule containing apharmaceutical formulation into a chamber in a body, rotating anendpiece relative to the body to connect the endpiece to the body, therotation being about an axis passing through the chamber, before,during, or after inserting the capsule into the chamber, providing anopening in the capsule, and inhaling through an opening in the endpieceto cause air to flow into the chamber through an inlet in the bodythereby aerosolizing the pharmaceutical formulation.

DRAWINGS

These features, aspects, and advantages of the present invention willbecome better understood with regard to the following description,appended claims, and accompanying drawings which illustrate exemplaryfeatures of the invention. However, it is to be understood that each ofthe features can be used in the invention in general, not merely in thecontext of the particular drawings, and the invention includes anycombination of these features, where:

FIG. 1 is a schematic sectional side view of a version of anaerosolization device of the invention with an endpiece and bodyconnected;

FIG. 2 is a schematic sectional side view of the version of anaerosolization device of FIG. 1 with the endpiece and body disconnected;

FIG. 3 is a schematic sectional side view of a version of anaerosolization device in use;

FIG. 4A is a schematic sectional side view of another version of anaerosolization device;

FIG. 4B is a schematic prospective view of the aerosolization device ofFIG. 4A;

FIG. 4C is a schematic section view along section A-A in FIG. 4B;

FIGS. 5A through 5C are schematic views of versions of connectionmechanisms for use with an aerosolization device;

FIG. 6A is a schematic sectional side view of a portion of anotherversion of an aerosolization device;

FIG. 6B is a schematic end view of the body of the version of anaerosolization device of FIG. 6A;

FIG. 6C is a schematic sectional side view of the version of theaerosolization device of FIG. 6A in a connected configuration;

FIGS. 7A and 7B are schematic sectional and schematic perspective views,respectively, of a portion of another version of an aerosolizationdevice;

FIG. 8 is a schematic perspective view of a portion of another versionof an aerosolization device;

FIG. 9 is a schematic side view of a body of a version of anaerosolization device;

FIG. 10 is a schematic sectional side view of a body of another versionof an aerosolization device; and

FIGS. 11A though 11M illustrate parts of a specific version of anaerosolization device.

DESCRIPTION

The present invention relates to delivering an aerosolizedpharmaceutical formulation to a patient. Although the process isillustrated in the context of aerosolizing a dry powder pharmaceuticalformulation, the present invention can be used in other processes andshould not be limited to the examples provided herein.

An aerosolization device 100 of the present invention is shownschematically in FIG. 1. The aerosolization device 100 includes a body105 and an endpiece 110 that may be attached to the body 105 to form achamber 115 within the interior of the body 105 and the endpiece 110.The endpiece 110 includes an end 120 defining an outlet 125. The end 120may be sized and shaped to be received in a user's mouth. Alternatively,the end 120 may be sized and shaped to be received in a nostril of auser or may sized and shaped to be received by a mask, a spacer chamber,a respirator circuit, or the like. The body includes one or more inlets130 in communication with the chamber 115. Together the inlets 130, thechamber 115, and the outlet 125 define an airway through theaerosolization device 100. Accordingly, when a user contacts theendpiece 110 and inhales or otherwise creates a vacuum at the outlet125, a pharmaceutical formulation with the chamber 115 may be deliveredto the user through the outlet 125. In one version, the pharmaceuticalformulation may be contained within a capsule that is positionablewithin the chamber 115, the chamber 115 being sized to receive thecapsule in a manner which allows the capsule to move within the chamber115. In this version, the endpiece 110 includes a perforated member 135having one or more openings 140 therein. The perforated member 135sufficiently blocks the chamber 115 to retain a capsule in the chamber115, while the openings 140 allow air and/or other material to pass tothe outlet 125. A connection mechanism 150 may be provided to allow theendpiece 110 to be attached to the body 105.

In one version, as shown in FIG. 2, the connection mechanism 150 mayallow the body 105 and the endpiece 110 to be disconnected to allow foraccess to the chamber 115. In this version, the endpiece 110 may bedisconnected from the body 105 to allow a pharmaceutical formulation tobe inserted into the chamber, for example by allowing a capsule to beinserted into the chamber 115. In this version, the connection mechanismincludes a body connection member 150 athat cooperates with an endpiececonnection member 150 b to selectively connect and disconnect theendpiece 110 to the body 105.

After a capsule 160 has been inserted into the chamber 115, the endpiece110 may again be attached to the body 105 to secure the capsule 160within the chamber 115, as shown in FIG. 3. The capsule 160 is opened,for example by puncturing the capsule 160 prior to insertion or withinthe chamber 115, such as by longitudinally advancing a sliding puncturemechanism 162. When opened, the pharmaceutical formulation in thecapsule is allowed to exit the capsule 160. In one version, thepharmaceutical formulation is in a dry powder form and the flow of airthrough the airway causes the pharmaceutical formulation to beaerosolized. For example, as shown in FIG. 3, a user may contact theendpiece 110 with his or her mouth and inhale, thereby drawing airthrough the outlet 125, as shown by arrow 165. This inhalation causesair to be taken in through the inlets 130, as shown by arrows 170. Theair taken in causes the capsule 160 to agitate within the chamber 115.The agitation causes the dry powder pharmaceutical formulation to leavethe capsule 160 and become aerosolized in the airway. The aerosolizedpharmaceutical formulation passes through the perforated member 135 andis delivered to the user where it may be inhaled to a position in theuser's respiratory tract. In one particular embodiment, a plurality ofinlets 130 may be designed to cause the inlet air 170 to swirl withinthe chamber, for example, by being at least partially tangentiallyoriented as described in U.S. Pat. Nos. 4,995,385 and 4,069,819, both ofwhich are incorporated herein by reference in their entireties. In suchan arrangement, the chamber 115 comprises a longitudinal axis that liesgenerally in the inhalation direction 165, and the capsule 160 isinsertable lengthwise into the chamber 115 so that the capsule'slongitudinal axis may be parallel to the longitudinal axis of thechamber 115. The swirling air flow then causes the capsule to rotatewithin the chamber 115 in a manner where the longitudinal axis of thecapsule is remains at an angle less than 80 degrees, and preferably lessthan 45 degrees from the longitudinal axis of the chamber. In oneversion, this rotation is caused by the width of the chamber being lessthan the length of the capsule.

Often, a user will grasp the body 105 during use while inhaling throughthe endpiece 110. It has been discovered that doing so may create adisconnection force in the inhalation direction 165 between the body 105and the endpiece 110. Accordingly, the connection mechanism 150 may bedesigned to prevent undesired disconnection of the endpiece 110 from thebody 105 during use.

In one version, the connection mechanism 150 requires a force to beapplied at least partially in a direction other than in an inhalationdirection 165 in order to disconnect the endpiece 110 from the body 105.Thus, in this version, the user's inadvertent forcing apart of theendpiece 110 and the body 105 during use does not generate a force inthe direction required for disconnection. For example, the forcerequired for disconnection may be a rotational force. In oneparticularly preferred version, the rotational force is a rotationalforce applied about an axis that passes through the chamber. Forexample, the rotational force may be applied about an axis that passesthrough the chamber and is parallel or coaxial with a longitudinal axispassing through the chamber. Such a rotational force is generally notgenerated by a user during inhalation making inadvertent disconnectionmore difficult. Examples of connection mechanisms of this type areschematically shown in FIGS. 4-10.

In the version of FIGS. 4A, 4B, and 4C the aerosolization device 100comprises a connection mechanism 150 including a protrusion 175 on theendpiece 110 and a groove or slot 180 on the body 105. Alternatively,the protrusion 175 may be provided on the body 105 and the slot 180 maybe provided on the endpiece 110. The protrusion 175 is insertable intothe slot 180 for attachment of the endpiece 110 to the body 105. Forexample, in the version shown, the slot 180 may comprise alongitudinally extending portion 185 and a transversely extendingportion 190. To connect the parts, the protrusion 175 is inserted intothe longitudinally extending portion 185 until it is in a position inalignment with the transversely extending portion 190 at which time theendpiece 110 is twisted relative to the body 105 to cause the protrusion175 to slide within the transversely extending portion 190. When theprotrusion 175 is within the transversely extending portion 190, thewalls of the transversely extending portion 190 prevent movement of theprotrusion 175, and thus movement of the endpiece 110 in the inhalationdirection 165. Accordingly, when the user inhales on the endpiece 110,the endpiece 110 is prevented from disconnecting with the body 105 as aresult of forces in the inhalation direction 165 alone. FIG. 4C is across-section along line A-A of the transversely extending portion 190.As shown, the transversely extending portion 190 extends partly aroundthe circumference of the body 105. Alternatively, the transverselyextending portion 190 may extend completely around the body 105 or to adifferent circumferential position than the position shown.

The slot 180 may further be designed to help secure the protrusion 175within the slot 180. For example, as shown in FIGS. 5A, 5B, and 5C, thetransversely extending portion 190 may include a member which serves tosecure the protrusion 175 within the transversely extending portion 190.In the version of FIG. 5A, a projection 195 such as a bump is providedon the base of the transversely extending portion 190. When sufficientrotational force is applied, the protrusion 175 may slide over theprojection 195 to be positioned in a secured position 200 in the slot180, thereby providing a snap fit. To disconnect the parts, the endpiece110 may be twisted in the opposite direction with sufficient force tocause the protrusion 175 to again slide past the projection 195.Additionally or alternatively, one or more projections 195 may beprovided on the side walls of the transversely extending portion 190. Inthe version of FIG. 5B, the depth of the base 205 of the transverselyextending portion 190 gradually lessens. Accordingly, as the protrusion175 is slid in the transversely extending portion 190, the frictionalforces increase and the protrusion 175 may be wedged into a secureposition within the slot 180. To disconnect this version, a sufficientforce is applied to overcome the wedging of the protrusion 175 in thetransversely extending portion 190. Alternatively, the side walls of thetransversely extending portion may be somewhat V-shaped to create thewedging effect. In the version shown in FIG. 5C, the slot 180 comprisesa second longitudinally extending portion 207 spaced from thelongitudinally extending portion 185 and communicable therewith by thetransversely extending portion 190. When in the forward region of thesecond longitudinally extending portion 207, the protrusion 175 isprevented from movement in the transverse direction and from movement inthe inhalation direction 165. Thus, force generated during inhalationdoes not cause disconnection. To disconnect, the endpiece is moved in adirection opposite to the inhalation direction 165. A projection or awedging surface, as discussed above, may be further provided in thesecond longitudinally extending portion 207 to further secure theprotrusion 175. Optionally, a biasing member, such as a compressedspring, may be positioned to bias the protrusion in the inhalationdirection 165 when the protrusion is in the slot 180. The biasing memberwill serve to secure the protrusion in the second longitudinallyextending portion 207 until the user applies a force sufficient toovercome the bias.

In another version, as shown for example in FIGS. 6A, 6B, and 6C, theaerosolization device 100 comprises a connection mechanism 150 with alongitudinally extending protrusion 210 that is receivable in aninterior slot 215. In the version shown, the longitudinal protrusion 210is provided on the endpiece 110 and the interior slot 215 is provided onthe body 105. Alternatively, this may be reversed. The interior slot 215includes a collar 220 which is receivable in a recess 225 on theprotrusion 210 to prevent movement of the endpiece 110 in the inhalationdirection 165 when the endpiece 110 is attached to the body 105, asshown in the connected configuration shown in FIG. 6C. A portion of thecollar 220 is reduced in size or thinned to provide a longitudinalaccess 230 to the slot 215, as best shown in FIG. 6B which is an endview of the body 105 along line BB. To attach the endpiece 110 to thebody 105 in this version, the protrusion 210 is inserted into thelongitudinal access 230 of the slot 215 until the end portion 235extends beyond the collar 220. The endpiece 110 is then twisted so thatthe end portion 235 is positioned behind the collar 220 and preventedfrom moving in the inhalation direction 165. A snap fit projection or asloped wedging surface, as discussed above, may be provided in the slot215 to further secure the protrusion 210 within the slot 215.Optionally, multiple protrusions and slots may be provided, as shown.

As can be seen in FIG. 6C, this version of the aerosolization device 100also provides a substantially smooth surface 240 within the chamber 115.This smooth surface 240 may be advantageous in increasing theaerosolization space in the chamber 115 thereby creating more space inwhich a capsule may rattle. Additionally, the less discontinuous surfacemay provide more consistent rattling of the capsule and, thus, moreconsistent emptying of the capsule. FIGS. 7A and 7B show another versionof a connection mechanism 150 that provides a smooth surface when in aconnected configuration. In this version, a longitudinal protrusion 245extends from the body 105 and is insertable into an opening 250 in theend surface 255 in the endpiece 110. Alternatively, the protrusion 245and opening 250 may be reversed. The opening 250 includes a collar 260that may be engaged around or near a recess 265 on the protrusion 245when in a connected configuration to prevent the endpiece 110 frommoving relative to the body 105 in the inhalation direction 165. Toconnect the parts, an end portion 270 of the protrusion 245 is insertedinto the opening 250 at an enlarged area 280, as best shown in FIG. 7B.The parts are then rotated relative to one another so that the endportion 270 is secured within a cavity 275 beyond the collar 260. Thecavity 275 may have snap fit projections or wedging surfaces, asdiscussed above, to further secure the protrusion 245 within the opening250. Multiple protrusions 245 and openings 250 may be provided.

In the versions of FIGS. 4 through 7, indicia may be provided to aid theuser when connecting or disconnecting the endpiece 110 to the body 105.For example, as shown in the version of FIG. 7B, a first marking 285 maybe provided on the outer surface of the endpiece 110 and a secondmarking 290 may be provided on the outer surface of the body 105. Whenthe first marking 285 and the second marking 290 are aligned with oneanother, the two parts may be disconnected. Additionally oralternatively, markings may be provided to indicate to the user in whichdirection to twist the parts in order to connect or to disconnect theparts.

Another version of an aerosolization device 100 comprising a connectionmechanism 150 that must at least partially be forced in a directionother than an inhalation direction 165 is shown in FIG. 8. In thisversion, the body 105 includes a male portion 300 that is insertableinto a female portion 305 on the endpiece 110. On the male portion 300are external threads 310 that may engage internal threads 315 on theendpiece 110. Accordingly, the endpiece 110 may be attached to the body105 by screwing the parts together. The threaded engagement prevents theendpiece 110 from disconnecting from the body 105 when a force in theinhalation direction 165 is applied. It has been discovered that thisarrangement prevents disconnection of the parts during inhalation by auser. Alternatively, the threaded arrangement shown in FIG. 8 may beswitched so that the male portion 300 is on the endpiece 110 and thefemale portion 305 is on the body 105. The threads may be standardhelical threads. Alternatively, the threads may comprise a series ofbumps and/or posts that mate in a screw-like manner.

The thread arrangement may be designed to further prevent disconnectionof the endpiece 110 from the body 105 during use. For example, FIG. 9shows a version of a threaded portion having threads of high pitch. Ithas been determined that when the thread angle, a, is less than about 9degrees, inhalation forces in the inhalation direction 165 are notsufficient to unscrew the parts. Accordingly, in one version, thethreads have a thread angle of less than about 9 degrees, and morepreferably less than about 7 degrees. Alternatively or additionally, thethreads may be shaped to further prevent disconnection of the endpiece110 and the body 105 when a force in the inhalation direction 165 isapplied. For example, in the version shown in FIG. 10, the threads havea recessed backside 320 to provide interlocking of the threads andthereby preventing stripping of the threads when stressed. In oneversion, the recess angle, b, is less than 90 degrees, more preferablyless than about 75 degrees, and most preferably less than about 60degrees. The mating threads on the opposing part are shaped to bereceived in the recessed backside 320.

FIGS. 11A though 11M illustrate parts from a specific version of anaerosolization device 100. FIGS. 11A and 11B show, respectively, asectional view and a side view of a cap 500 that may be inserted over anendpiece 110. FIGS. 11C and 11D show, respectively, a sectional view anda side view of a specific version 505 of a body 105. The versionincludes a plurality of angled slots 510 that provide an inlet 130 intothe chamber 115. FIGS. 11E and 11F show, respectively, a sectional viewand a side view of a version 515 of an endpiece 110. The endpiece 110may be connected and disconnect to the body 105 by rotational force.FIG. 11G shows an end view of the endpiece 110 of FIG. 11E showing anarcuate version 520 of a perforated member 135 within the endpiece 110.

FIGS. 11H and 11I show, respectively, a version 525 of a puncturingmechanism 162. A U-shaped puncturing member 530, as shown in FIG. 11J,is seated in the end of a slidable member 535. As shown in FIG. 11K, aposition 540 on the device may be used to provide a marking on thedevice. FIGS. 11L and 11K show, respectively, a sectional view and aside view of an assembled device according to the version of FIGS. 11Athrough 11J. To use the aerosolization device 100 of FIGS. 11A through11J, a user takes an assembled device, as shown in FIG. 11L, and removesthe cap 500. Then, the user twists the endpiece 515 to cause theinterior threads on the endpiece 515 to be separated from the exteriorthreads on the body 505 to disconnect the endpiece 515 from the body505, thereby providing access to the chamber 115 so that the user mayinsert a capsule containing a pharmaceutical formulation. Afterinsertion, the endpiece 515 is connected to the body by threadedengagement and the puncturing mechanism 525 is advanced to create one ormore openings into the capsule. The user then places his or her mouth ornose on the endpiece 515 and inhales through the endpiece 515. Theinhalation causes air to flow through the inlets 510 and into thechamber 115 where it causes the capsule to be swirled in a manner whichcauses the pharmaceutical formulation to be aerosolized. The aerosolizedpharmaceutical formulation then flows through the endpiece and into theuser's respiratory tract. The twist attachment of the endpiece 515 tothe body 505 prevents the inadvertent disconnection of the endpiece 515as a result of inhalation pressure and thereby reduces the risk ofinhalation of the endpiece 515.

In a preferred version, the invention provides a system and method foraerosolizing a pharmaceutical formulation and delivering thepharmaceutical formulation to the lungs of the user. The pharmaceuticalformulation may comprise powdered medicaments, liquid solutions orsuspensions, and the like, and may include an active agent.

The active agent described herein includes an agent, drug, compound,composition of matter or mixture thereof which provides somepharmacologic, often beneficial, effect. This includes foods, foodsupplements, nutrients, drugs, vaccines, vitamins, and other beneficialagents. As used herein, the terms further include any physiologically orpharmacologically active substance that produces a localized or systemiceffect in a patient. An active agent for incorporation in thepharmaceutical formulation described herein may be an inorganic or anorganic compound, including, without limitation, drugs which act on: theperipheral nerves, adrenergic receptors, cholinergic receptors, theskeletal muscles, the cardiovascular system, smooth muscles, the bloodcirculatory system, synoptic sites, neuroeffector junctional sites,endocrine and hormone systems, the immunological system, thereproductive system, the skeletal system, autacoid systems, thealimentary and excretory systems, the histamine system, and the centralnervous system. Suitable active agents may be selected from, forexample, hypnotics and sedatives, psychic energizers, tranquilizers,respiratory drugs, anticonvulsants, muscle relaxants, antiparkinsonagents (dopamine antagnonists), analgesics, anti-inflammatories,antianxiety drugs (anxiolytics), appetite suppressants, antimigraineagents, muscle contractants, anti-infectives (antibiotics, antivirals,antifungals, vaccines) antiarthritics, antimalarials, antiemetics,anepileptics, bronchodilators, cytokines, growth factors, anti-canceragents, antithrombotic agents, antihypertensives, cardiovascular drugs,antiarrhythmics, antioxicants, anti-asthma agents, hormonal agentsincluding contraceptives, sympathomimetics, diuretics, lipid regulatingagents, antiandrogenic agents, antiparasitics, anticoagulants,neoplastics, antineoplastics, hypoglycemics, nutritional agents andsupplements, growth supplements, antienteritis agents, vaccines,antibodies, diagnostic agents, and contrasting agents. The active agent,when administered by inhalation, may act locally or systemically.

The active agent may fall into one of a number of structural classes,including but not limited to small molecules, peptides, polypeptides,proteins, polysaccharides, steroids, proteins capable of elicitingphysiological effects, nucleotides, oligonucleotides, polynucleotides,fats, electrolytes, and the like.

Examples of active agents suitable for use in this invention include butare not limited to one or more of calcitonin, erythropoietin (EPO),Factor VIII, Factor IX, ceredase, cerezyme, cyclosporin, granulocytecolony stimulating factor (GCSF), thrombopoietin (TPO), alpha-1proteinase inhibitor, elcatonin, granulocyte macrophage colonystimulating factor (GMCSF), growth hormone, human growth hormone (HGH),growth hormone releasing hormone (GHRH), heparin, low molecular weightheparin (LMWH), interferon alpha, interferon beta, interferon gamma,interleukin-1 receptor, interleukin-2, interleukin-1 receptorantagonist, interleukin-3, interleukin-4, interleukin-6, luteinizinghormone releasing hormone (LHRH), factor IX, insulin, pro-insulin,insulin analogues (e.g., mono-acylated insulin as described in U.S. Pat.No. 5,922,675, which is incorporated herein by reference in itsentirety), amylin, C-peptide, somatostatin, somatostatin analogsincluding octreotide, vasopressin, follicle stimulating hormone (FSH),insulin-like growth factor (IGF), insulintropin, macrophage colonystimulating factor (M-CSF), nerve growth factor (NGF), tissue growthfactors, keratinocyte growth factor (KGF), glial growth factor (GGF),tumor necrosis factor (TNF), endothelial growth factors, parathyroidhormone (PTH), glucagon-like peptide thymosin alpha 1, IIb/IIIainhibitor, alpha-1 antitrypsin, phosphodiesterase (PDE) compounds, VLA-4inhibitors, bisphosponates, respiratory syncytial virus antibody, cysticfibrosis transmembrane regulator (CFTR) gene, deoxyreibonuclease(Dnase), bactericidal/permeability increasing protein (BPI), anti-CMVantibody, 13-cis retinoic acid, macrolides such as erythromycin,oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin,azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin,midecamycin, leucomycin, miocamycin, rokitamycin, andazithromycin, andswinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin,levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin, norfloxacin,enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin,temafloxacin, pefloxacin, amifloxacin, fleroxacin, tosufloxacin,prulifloxacin, irloxacin, pazufloxacin, clinafloxacin, and sitafloxacin,aminoglycosides such as gentamicin, netilmicin, paramecin, tobramycin,amikacin, kanamycin, neomycin, and streptomycin, vancomycin,teicoplanin, rampolanin, mideplanin, colistin, daptomycin, gramicidin,colistimethate, polymixins such as polymixin B, capreomycin, bacitracin,penems; penicillins including penicllinase-sensitive agents likepenicillin G, penicillin V, penicillinase-resistant agents likemethicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin,nafcillin; gram negative microorganism active agents like ampicillin,amoxicillin, and hetacillin, cillin, and galampicillin; antipseudomonalpenicillins like carbenicillin, ticarcillin, azlocillin, mezlocillin,and piperacillin; cephalosporins like cefpodoxime, cefprozil, ceftbuten,ceftizoxime, ceftriaxone, cephalothin, cephapirin, cephalexin,cephradrine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor,cefadroxil, cephaloglycin, cefuroxime, ceforanide, cefotaxime,cefatrizine, cephacetrile, cefepime, cefixime, cefonicid, cefoperazone,cefotetan, cefinetazole, ceftazidime, loracarbef, and moxalactam,monobactams like aztreonam; and carbapenems such as imipenem, meropenem,pentamidine isethiouate, albuterol sulfate, lidocaine, metaproterenolsulfate, beclomethasone diprepionate, triamcinolone acetamide,budesonide acetonide, fluticasone, ipratropium bromide, flunisolide,cromolyn sodium, ergotamine tartrate and where applicable, analogues,agonists, antagonists, inhibitors, and pharmaceutically acceptable saltforms of the above. In reference to peptides and proteins, the inventionis intended to encompass synthetic, native, glycosylated,unglycosylated, pegylated forms, and biologically active fragments andanalogs thereof.

Active agents for use in the invention further include nucleic acids, asbare nucleic acid molecules, vectors, associated viral particles,plasmid DNA or RNA or other nucleic acid constructions of a typesuitable for transfection or transformation of cells, i.e., suitable forgene therapy including antisense. Further, an active agent may compriselive attenuated or killed viruses suitable for use as vaccines. Otheruseful drugs include those listed within the Physician's Desk Reference(most recent edition).

The amount of active agent in the pharmaceutical formulation will bethat amount necessary to deliver a therapeutically effective amount ofthe active agent per unit dose to achieve the desired result. Inpractice, this will vary widely depending upon the particular agent, itsactivity, the severity of the condition to be treated, the patientpopulation, dosing requirements, and the desired therapeutic effect. Thecomposition will generally contain anywhere from about 1% by weight toabout 99% by weight active agent, typically from about 2% to about 95%by weight active agent, and more typically from about 5% to 85% byweight active agent, and will also depend upon the relative amounts ofadditives contained in the composition. The compositions of theinvention are particularly useful for active agents that are deliveredin doses of from 0.001 mg/day to 100 mg/day, preferably in doses from0.01 mg/day to 75 mg/day, and more preferably in doses from 0.10 mg/dayto 50 mg/day. It is to be understood that more than one active agent maybe incorporated into the formulations described herein and that the useof the term “agent” in no way excludes the use of two or more suchagents.

The pharmaceutical formulation may comprise a pharmaceuticallyacceptable excipient or carrier which may be taken into the lungs withno significant adverse toxicological effects to the subject, andparticularly to the lungs of the subject. In addition to the activeagent, a pharmaceutical formulation may optionally include one or morepharmaceutical excipients which are suitable for pulmonaryadministration. These excipients, if present, are generally present inthe composition in amounts ranging from about 0.01% to about 95% percentby weight, preferably from about 0.5 to about 80%, and more preferablyfrom about 1 to about 60% by weight. Preferably, such excipients will,in part, serve to further improve the features of the active agentcomposition, for example by providing more efficient and reproducibledelivery of the active agent, improving the handling characteristics ofpowders, such as flowability and consistency, and/or facilitatingmanufacturing and filling of unit dosage forms. In particular, excipientmaterials can often function to further improve the physical andchemical stability of the active agent, minimize the residual moisturecontent and hinder moisture uptake, and to enhance particle size, degreeof aggregation, particle surface properties, such as rugosity, ease ofinhalation, and the targeting of particles to the lung. One or moreexcipients may also be provided to serve as bulking agents when it isdesired to reduce the concentration of active agent in the formulation.

Pharmaceutical excipients and additives useful in the presentpharmaceutical formulation include but are not limited to amino acids,peptides, proteins, non-biological polymers, biological polymers,carbohydrates, such as sugars, derivatized sugars such as alditols,aldonic acids, esterified sugars, and sugar polymers, which may bepresent singly or in combination. Suitable excipients are those providedin WO 96/32096, which is incorporated herein by reference in itsentirety. The excipient may have a glass transition temperatures (Tg)above about 35° C., preferably above about 40° C., more preferably above45° C., most preferably above about 55° C.

Exemplary protein excipients include albumins such as human serumalbumin (HSA), recombinant human albumin (rHA), gelatin, casein,hemoglobin, and the like. Suitable amino acids (outside of thedileucyl-peptides of the invention), which may also function in abuffering capacity, include alanine, glycine, arginine, betaine,histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine,isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine,tryptophan, and the like. Preferred are amino acids and polypeptidesthat function as dispersing agents. Amino acids falling into thiscategory include hydrophobic amino acids such as leucine, valine,isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine,histidine, and proline. Dispersibility enhancing peptide excipientsinclude dimers, trimers, tetramers, and pentamers comprising one or morehydrophobic amino acid components such as those described above.

Carbohydrate excipients suitable for use in the invention include, forexample, monosaccharides such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitolsorbitol (glucitol), pyranosyl sorbitol, myoinositol and the like.

The pharmaceutical formulation may also include a buffer or a pHadjusting agent, typically a salt prepared from an organic acid or base.Representative buffers include organic acid salts of citric acid,ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinicacid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride,or phosphate buffers. The pharmaceutical formulation may also includepolymeric excipients/additives, e.g., polyvinylpyrrolidones, derivatizedcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, andhydroxypropylmethylcellulose, Ficolls (a polymeric sugar),hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin),polyethylene glycols, and pectin.

The pharmaceutical formulation may further include flavoring agents,taste-masking agents, inorganic salts (for example sodium chloride),antimicrobial agents (for example benzalkonium chloride), sweeteners,antioxidants, antistatic agents, surfactants (for example polysorbatessuch as “TWEEN 20” and “TWEEN 80”), sorbitan esters, lipids (for examplephospholipids such as lecithin and other phosphatidylcholines,phosphatidylethanolamines), fatty acids and fatty esters, steroids (forexample cholesterol), and chelating agents (for example EDTA, zinc andother such suitable cations). Other pharmaceutical excipients and/oradditives suitable for use in the compositions according to theinvention are listed in “Remington: The Science & Practice of Pharmacy”,19^(th) ed., Williams & Williams, (1995), and in the “Physician's DeskReference”, 52^(nd) ed., Medical Economics, Montvale, N.J. (1998), bothof which are incorporated herein by reference in their entireties. “Massmedian diameter” or “MMD” is a measure of mean particle size, since thepowders of the invention are generally polydisperse (i.e., consist of arange of particle sizes). MMD values as reported herein are determinedby centrifugal sedimentation, although any number of commonly employedtechniques can be used for measuring mean particle size. “Mass medianaerodynamic diameter” or “MMAD” is a measure of the aerodynamic size ofa dispersed particle. The aerodynamic diameter is used to describe anaerosolized powder in terms of its settling behavior, and is thediameter of a unit density sphere having the same settling velocity,generally in air, as the particle. The aerodynamic diameter encompassesparticle shape, density and physical size of a particle. As used herein,MMAD refers to the midpoint or median of the aerodynamic particle sizedistribution of an aerosolized powder determined by cascade impaction.

In one version, the powdered formulation for use in the presentinvention includes a dry powder having a particle size selected topermit penetration into the alveoli of the lungs, that is, preferably 10μm mass median diameter (MMD), preferably less than 7.5 μm, and mostpreferably less than 5 μm, and usually being in the range of 0.1 μm to 5μm in diameter. The delivered dose efficiency (DDE) of these powders maybe greater than 30%, more preferably greater than 40%, more preferablygreater than 50% and most preferably greater than 60% and the aerosolparticle size distribution is about 1.0-5.0 μm mass median aerodynamicdiameter (MMAD), usually 1.5-4.5 μm MMAD and preferably 1.5-4.0 μm MMAD.These dry powders have a moisture content below about 10% by weight,usually below about 5% by weight, and preferably below about 3% byweight. Such powders are described in WO 95/24183, WO 96/32149, WO99/16419, and WO 99/16422, all of which are all incorporated herein byreference in their entireties.

Although the present invention has been described in considerable detailwith regard to certain preferred versions thereof, other versions arepossible, and alterations, permutations and equivalents of the versionshown will become apparent to those skilled in the art upon a reading ofthe specification and study of the drawings. For example, thecooperating components may be reversed or provided in additional orfewer number. Also, the various features of the versions herein can becombined in various ways to provide additional versions of the presentinvention. Furthermore, certain terminology has been used for thepurposes of descriptive clarity, and not to limit the present invention.Therefore, the appended claims should not be limited to the descriptionof the preferred versions contained herein and should include all suchalterations, permutations, and equivalents as fall within the truespirit and scope of the present invention.

What is claimed is:
 1. An aerosolization apparatus comprising: a body having an inlet; an endpiece having an outlet, the endpiece being connectable to the body to define a chamber, wherein the chamber is sized to receive a capsule containing a pharmaceutical formulation in a manner which allows the capsule to move within the chamber and wherein the inlet is shaped to provide a swirling air flow in the chamber; a connection mechanism comprising engageable threads to provide selective connection of the endpiece to the body, wherein a rotational force between the endpiece and the body is needed to connect and to disconnect the endpiece from the body, the rotational force being applied about an axis passing through the chamber, wherein the endpiece may be disconnected from the body to allow for insertion or removal of the capsule, and wherein the threads extend for less than two complete turns around the body; a cap insertable over the endpiece and which covers at least a portion of the inlet when the endpiece is connected to the body, wherein the cap is connectable to the body by a press fit arrangement; and a puncturing mechanism capable of providing an opening in the capsule; whereby when a user inhales, air enters into the chamber through the inlet so that the pharmaceutical formulation is aerosolized within the chamber and the aerosolized pharmaceutical formulation is delivered to the user through the outlet.
 2. An aerosolization apparatus according to claim 1 wherein the body has a plurality of inlets.
 3. An aerosolization apparatus according to claim 1 wherein the connection mechanism comprises engageable threads having a thread angle of less than about 9 degrees.
 4. An aerosolization apparatus according to claim 1 wherein the connection mechanism comprises engageable threads having a thread angle of less than about 7 degrees.
 5. An aerosolization apparatus according to claim 1 wherein the connection mechanism comprises engageable threads and wherein the threads include a recessed portion.
 6. An aerosolization apparatus according to claim 1 wherein the connection mechanism comprises engageable threads and wherein the threads include a recessed portion that is recessed at an angle of less than about 75 degrees.
 7. An aerosolization apparatus according to claim 1 wherein the puncturing mechanism is adapted to puncture a single end of the capsule.
 8. An apparatus according to claim 1 wherein the chamber is elongated and has a longitudinal axis, and wherein the longitudinal axis of the chamber and the longitudinal axis of the capsule form an angle of less than about 45 degrees during use.
 9. An apparatus according to claim 1 wherein the chamber is elongated and wherein the capsule is received lengthwise within the elongated chamber.
 10. An aerosolization apparatus according to claim 1 wherein the width of the chamber is less than the length of the capsule.
 11. An aerosolization apparatus according to claim 1 further comprising the capsule containing the pharmaceutical formulation and wherein the pharmaceutical formulation comprises an antibiotic.
 12. An aerosolization apparatus according to claim 11 wherein the antibiotic comprises an aminoglycoside.
 13. An aerosolization apparatus according to claim 12 wherein the aminoglycoside comprises tobramycin.
 14. An aerosolization apparatus according to claim 11 wherein the antibiotic comprises a fluoroquinolone.
 15. An aerosolization apparatus according to claim 14 wherein the fluoroquinolone comprises ciprofloxacin.
 16. An aerosolization apparatus comprising: a body having an inlet; an endpiece having an outlet, the endpiece being connectable to the body to define a chamber, wherein the chamber is sized to receive a capsule containing a pharmaceutical formulation in a manner which allows the capsule to move within the chamber and wherein the inlet is shaped to provide a swirling air flow in the chamber; a cap that is insertable over the endpiece and that covers at least a portion of the inlet when the endpiece is connected to the body, wherein the cap is connectable to the body by a press fit arrangement; a connection mechanism to provide selective connection of the endpiece to the body, wherein the connection mechanism comprises engageable threads, and wherein the endpiece may be disconnected from the body to allow for insertion or removal of the capsule; and a puncturing mechanism capable of providing an opening in the capsule; whereby when a user inhales, air enters into the chamber through the inlet so that the pharmaceutical formulation is aerosolized within the chamber and the aerosolized pharmaceutical formulation is delivered to the user through the outlet.
 17. An aerosolization apparatus according to claim 16 wherein the engageable threads have a thread angle of less than about 9 degrees.
 18. An aerosolization apparatus according to claim 16 wherein the engageable threads have a thread angle of less than about 7 degrees.
 19. An aerosolization apparatus according to claim 16 wherein the engageable threads include a recessed portion.
 20. An aerosolization apparatus according to claim 16 wherein the engageable threads include a recessed portion that is recessed at an angle of less than about 75 degrees.
 21. An aerosolization apparatus according to claim 16 further comprising the capsule containing the pharmaceutical formulation and wherein the pharmaceutical formulation comprises an antibiotic.
 22. An aerosolization apparatus according to claim 21 wherein the antibiotic comprises an aminoglycoside.
 23. An aerosolization apparatus according to claim 22 wherein the aminoglycoside comprises tobramycin.
 24. An aerosolization apparatus according to claim 21 wherein the antibiotic comprises a fluoroquinolone.
 25. An aerosolization apparatus according to claim 24 wherein the fluoroquinolone comprises ciprofloxacin.
 26. An aerosolization apparatus according to claim 16 wherein the cap is threadless.
 27. A method of providing an aerosolized pharmaceutical formulation, the method comprising: providing a body having an inlet and providing an endpiece having an outlet, the endpiece and the body having engageable threads that extend less than two complete turns, the endpiece being connectable to and disconnectable from the body when a rotational force is applied thereto to define a chamber, the chamber being sized to receive a capsule containing a pharmaceutical formulation, wherein the rotational force is applied about an axis that passes through the chamber, and wherein the endpiece may be disconnected from the body to allow for insertion or removal of the capsule; providing a cap that may be removed from the endpiece by disconnecting a press fit arrangement to expose the inlet; and aerosolizing the pharmaceutical formulation when a user inhales by causing air to flow through an inlet in the body, within the chamber, and through an outlet in the endpiece to provide the aerosolized pharmaceutical formulation to the user and wherein the inlet is shaped to provide a swirling air flow in the chamber.
 28. A method according to claim 27 wherein the threads have a thread angle of less than about 7 degrees.
 29. A method according to claim 27 wherein the threads have a recessed portion.
 30. A method according to claim 27 wherein the pharmaceutical formulation comprises a dry powder.
 31. A method of aerosolizing a pharmaceutical formulation, the method comprising: removing a cap from an endpiece by disconnecting a press fit arrangement to exposed an inlet; rotating the endpiece relative to a body to expose a chamber in the body, wherein the body contains the inlet; inserting a capsule containing a pharmaceutical formulation into the chamber in the body; thereafter, rotating the endpiece relative to the body to connect the endpiece to the body, the rotation being about an axis passing through the chamber; before, during, or after inserting the capsule into the chamber, providing an opening in the capsule; inhaling through an opening in the endpiece to cause air to flow into the chamber through an inlet in the body thereby aerosolizing the pharmaceutical formulation, wherein the flow of air through the inlet causes a swirling flow in the chamber.
 32. A method according to claim 31 wherein the chamber is elongated and wherein the capsule is inserted lengthwise into the elongated chamber.
 33. A method according to claim 31 wherein the flow of air is through a plurality of inlets in the body.
 34. A method according to claim 31 wherein the flow of air is through a plurality of inlets in the body.
 35. A method of aerosolizing a pharmaceutical formulation, the method comprising: inserting a capsule containing a pharmaceutical formulation into a chamber in a body; thereafter, rotating an endpiece relative to the body to connect the endpiece to the body by engageable threads, the rotation being about an axis passing through the chamber and complete rotation being less than two turns; before, during, or after inserting the capsule into the chamber, providing an opening in the capsule; inhaling through an opening in the endpiece to cause air to flow into the chamber through an inlet in the body thereby aerosolizing the pharmaceutical formulation, wherein the flow of air through the inlet causes a swirling flow in the chamber; and thereafter, rotating the endpiece relative to the body to disconnect the endpiece from the body and expose the chamber; thereafter, rotating the endpiece relative to the body to reconnect the endpiece to the body; and thereafter, installing a cap over the endpiece to cover at least a portion of the in inlet by connecting the cap to the body by a press fit arrangement. 